Pharmacological manipulations which attenuate the behavioral effects of amphetamine (AMPH) and cocaine (COC) have potential to be important agents for modifying the abuse potential of psychostimulants. The behavioral effects of AMPH are dependent on activation of dopamine (DA) receptors in the striatum and limbic forebrain, and are modulated by the A2 subtype of adenosine receptor. A2 receptors are expressed abundantly and exclusively in forebrain areas enriched in DA receptors. We have recently isolated the rat A2 adenosine receptor cDNA. We are now able to test the hypothesis that modulation of the behavioral effects of AMPH by A2 receptors results from co-activation of A2 and DA receptors residing on a subset of forebrain neurons and subsequent modulation of post-receptor cellular responses in those neurons. Similar cellular mechanisms may underlie the modulatory effects of adenosinergic agents on the behavioral effects of COC. The goals of this grant are to identify the anatomical systems in striatum and limbic forebrain in which A2 and AI adenosine receptors overlap with DA receptors and to determine if modulation of immediate early genes may be a marker of a subset of forebrain neurons in which a functional interaction between adenosine receptors and AMPH occurs. These experiments will begin to identify nuclear mechanisms which underlie the interactions of A2 receptors and psychostimulants. Three aims are proposed: (1) Determine the localization of A2 receptor mRNA with neurons expressing DA receptor genes and with other neurochemical markers within the striatum and limbic forebrain, (2) Identify the cell types in the striatum and limbic forebrain which express the AI adenosine receptor gene, and (3) Determine whether forebrain A2 adenosine receptors are linked to the same immediate early genes as AMPH. Study of the forebrain A2 adenosine receptor may lead to the identification of anatomical circuits and cellular mechanisms, and novel strategies for their independent regulation, which modulate the rewarding properties of psychostimulants and, more generally, activity of the dopaminergic system in brain.